Compounds for the treatment of hemophilia

ABSTRACT

A compound of general formula (III′), or one of its pharmaceutically acceptable salts, for its use for the treatment of hemophilia in a subject, in particular for the restoration of coagulation in the plasma of a subject suffering from hemophilia, this compound being advantageously administered by oral route:

The present invention falls within the therapeutic field, morespecifically in the field of the treatment of hemophilia.

More specifically, the present invention concerns a compound ofparticular chemical structure, for its use for the treatment ofhemophilia.

Hemophilia is a rare genetic disease resulting in an impossibility forthe blood to clot, and whose symptoms are spontaneous and repetitivepost-traumatic bleeding in the joints and muscles. This bleeding canresult in severe bleeding, whose consequences can be particularlyserious.

There are two types of hemophilia: hemophilia type A, due to adeficiency of the coagulation factor FVIII, which is the most commontype of hemophilia, and hemophilia type B, due to a deficiency of thecoagulation factor FIX. These deficiencies in coagulation factor FVIIIor FIX lead to a direct blockage of the intrinsic tenase complex, sothat, to produce the factor FXa, which generates thrombin and which isessential for the formation of blood clots and therefore forcoagulation, hemophiliac patients depend solely on the extrinsic pathwayof coagulation, and therefore on the extrinsic tenase complex. Thiscomplex, composed of tissue factor (TF) and coagulation factor FVIIa,allows the activation of the factor FX into FXa. FXa can then beassociated with the factor Va to form the prothrombinase, whichaccelerates the transformation of prothrombin into thrombin necessaryfor coagulation. However, the extrinsic tenase complex is also inhibitedin hemophiliac subjects by the binding of a protein, called TissueFactor Pathway Inhibitor (TFPI), to the FXa factor and to the complexTF-FVIIa-FXa.

TFPI is a protein that exists in two isoforms, alpha and beta. The alphaisoform contains an N-terminal end of 22 residues, followed by threeKunitz domains (K1, K2, K3) and then a long negatively chargedC-terminal end. The beta isoform lacks a K3 domain and is terminated bya different C-terminal end. The three-dimensional structure of eachKunitz domain is experimentally known. In the TFPI-TF-FVIIa-FXa complex,the generally recognized hypothesis is that the K2 domain of TFPI bindsto the active site of FXa and the K1 domain of TFPI binds to the activesite of FVIIa, as described in particular in the publication from Girardet al., 1989, Nature 338(6215), 518-20.

At present, hemophilia is systematically treated by replacementtherapies, consisting of intravenous injections, in the subject affectedby the disease, of the missing factors FVIII or FIX. These treatments,in addition to their binding mode of administration, have thedisadvantage of generating antibodies.

New therapeutic strategies currently under development, such as thatdescribed in the publication by Franchini et al., 2018, Bloodtransfusion, 16, 457-461, are based on the use of proteins which eitherincrease coagulation, such as emicizumab, a bispecific monoclonalantibody, restoring the coagulation equivalently to 10 to 20 IU/dL (10to 20%) of factor VIII, but which can under certain conditions beresponsible for thrombotic accidents, or blocks the main anticoagulantsof the coagulation cascade, in particular TFPI. The Concizumab, ananti-TFPI monoclonal antibody, has in particular been proposed as aninhibitor of TFPI.

The present invention aims to provide a treatment for hemophilia thatdoes not in particular have the disadvantages of antibody/protein-basedtreatments, this treatment making it possible to effectively restorecoagulation in patients affected by the disease, preferably beingadministered by oral route.

Additional objects of the invention are that this treatment beinexpensive and easy to produce and administer, and that it causes fewor no undesirable side effects.

The present inventors have now discovered that these objectives can beachieved by particular chemical molecules, derived from adamantane, anddefined by a particular general formula.

Thus, the present invention concerns a compound of formula (III′) below,or one of its pharmaceutically acceptable salts, for its use, as anactive agent, for the treatment of hemophilia in a subject sufferingfrom illness:

in which

Y₁′ represents a covalent bond or an amide group,

R₄′ represents a hydrogen atom, a hydroxyl group, a halogen atom, anamine group or a linear or branched, saturated or unsaturated carbonradical, which is optionally interrupted and/or substituted by one ormore heteroatoms and/or one or more several groups including at leastone heteroatom,

Y₂′ represents a covalent bond or an amide group,

A₂′ represents an optionally substituted cyclic or heterocyclic groupincluding two fused rings, at least one of said rings being aromatic.

When Y₁′ represents an amide group, the nitrogen atom of this group canbe linked to the adamantyl unit as well as to the phenyl radical.

Similarly, when Y₂′ represents an amide group, the nitrogen atom of thisgroup may just as well be bonded to the phenyl radical as to the groupA₂′.

In the present description, the term treatment is understood to mean acurative treatment of the bleeding episodes linked to the disease, andin particular the reduction and/or inhibition of the development of atleast one of the associated symptoms, in particular the improvement ofclotting and decrease in the amount and/or frequency of bleeding.

The subject treated according to the invention is in particular amammal, for example a non-human mammal. It is preferably a human being.

The compound used according to the invention advantageously makes itpossible to restore coagulation, by restoring the generation ofthrombin, in the plasma of a subject suffering from hemophilia, of typeA as well as of type B, including for subjects affected by severe formsof the disease.

In particular, it has been discovered by the present inventors that thecompound according to the invention, subjected to an ex vivo test forthe generation of fluorimetric thrombin, on the plasma of subjectssuffering from severe hemophilia A, allows, at a dose of 50 μM, torestore the generation of thrombin equivalent to FVIII and even higherdepending on the conditions.

The mechanisms underlying such an advantageous effect of the compoundused according to the invention will not be prejudged here. It mayhowever be thought that this effect could be due, at least in part, toan inhibition, by the compound according to the invention, in particularthe compound of general formula (III′) or one of its salts, of thebinding of the tissue factor pathway inhibitor (TFPI) to the coagulationfactor FXa.

The compound used according to the invention does not present anytoxicity for mammals. It can advantageously be administered orally, muchmore simply than the proteins used by the prior art, which must in turnbe administered by injection.

The compound according to the invention, and its pharmaceuticallyacceptable salts, by their chemical nature and their low molecularweight, generally less than 5 kDa and even, for certain combinations ofsubstituents, less than 1 kDa, or even less than 500 Da, are inparticular much easier, and less expensive, to prepare than theprotein/antibody compounds proposed by the prior art for the treatmentof hemophilia. In this respect, the compound according to the inventioncan be prepared by any synthesis method conventional in itself for thoseskilled in the art.

In the present description, the term «pharmaceutically acceptable salt»means any salt of the compound that does not cause any adverse, allergiceffect or other undesirable reaction when it is administered to thesubject, in particular to a human subject.

Any non-toxic conventional salt of the compound of general formula(III′) can be used according to the invention, for example a metallicsalt such as a sodium, potassium, magnesium, calcium, lithium, etc.salt. Alternatively, a salt formed from organic or inorganic acids maybe used, for example salts derived from inorganic acids such ashydrochloric, hydrobromic, phosphoric, sulfuric, etc. acids, and saltsderived from organic acids such as acetic, trifluoroacetic, propionic,maleic, benzoic, stearic, etc. acids. The salt can be synthesized, fromthe compound of general formula (III′), according to any chemical methodconventional in itself.

All the properties described in the present description for the compoundof general formula (III′) are also applied to its pharmaceuticallyacceptable salts.

The general formula (III′) above further encompasses all possiblecombinations of isomeric forms at the asymmetric carbons, and allmixtures of such isomeric forms. From a mixture of isomers, eachparticular isomer can be obtained by purification methods conventionalin themselves for those skilled in the art.

Preferably, in the general formula (III′), R₄′ represents an —OR₈ groupor an —O—CO—R₈ group, where R₈ represents a linear or branched,saturated or unsaturated hydrocarbon radical, in particular alkyl,including from 1 to 10 carbon atoms, optionally substituted by one ortwo identical or different substituents R₁₄, R₁₄′, each selected from—F, —CO₂H, —SO₃H, —P(O)(OH)₂, —P(O)(OCH₃)₂, —P(O)(OCH₂CH₃)₂, —N(CH₃)₂,—N(CH₂—CH₃)₂,

where R15 represents a hydrogen atom or a methyl group. R₈ may inparticular represent a group of general formula (XVIII):

in which y is an integer comprised between 1 and 10 and R₁₄ is asdefined above.

In particular embodiments of the invention, in the general formula(III′), R₄′ is fixed to the phenyl radical in the ortho or para positionwith respect to the adamantyl unit, and Y₂′ is fixed to the phenylradical in the meta position relative to the adamantyl motif.

Preferably, in general formula (III′), A₂′ is at least substituted byone substituent R₁₁ selected from fluorine, carboxyl, sulphonyl,phosphonyl, tetrazole or keto-oxadiazole groups, and linear, branchedand/or cyclic, saturated or unsaturated, aromatic or not carbonradicals, which are optionally interrupted and/or substituted by one ormore heteroatoms, in particular fluorine, and/or one or more groupscomprising at least one heteroatom, in particular carboxyl —CO₂H,sulfonyl —SO₃H and/or phosphonyl —P(O)(OH)₂.

R₁₁ can in particular be selected from tetrazole or keto-oxadiazolegroups of respective formulas:

In particular embodiments of the invention, the compound used for thetreatment of hemophilia corresponds to the general formula (IX):

in which

Y₁′, Y₂′ and R₄′ are as defined above,

A₃ represents a cyclic or 3- to 8-membered heterocyclic, saturated orunsaturated, aromatic or not hydrocarbon, which is fused to the adjacentsix-membered aromatic ring,

B₁ and B₂, which are identical or different, each represent a —CH— groupor a nitrogen atom,

R₉ and R₁₀, identical or different, each represent a hydrogen atom, ahydroxyl group or an —OR₁₂ or —CO—O—R₁₂ group where R₁₂ represents alinear or branched, saturated or unsaturated hydrocarbon radical, inparticular alkyl, including 1 to 10 carbon atoms, optionally substitutedby one or two identical or different substituents R₁₆, R₁₆′, eachselected from —F, —CO₂H, —SO₃H, —P(O)(OH)₂, —P(O)(OCH₃)₂,—P(O)(OCH₂CH₃)₂, —N(CH₃)₂, —N(CH₂—CH₃)₂,

where R₁₇ represents a hydrogen atom or a methyl group,and R₁₁ represents a substituent selected from fluorine, carboxyl,sulphonyl, phosphonyl, tetrazole or keto-oxadiazole groups, and linear,branched and/or cyclic, saturated or unsaturated, aromatic ornon-aromatic carbon radicals, which are optionally interrupted and/orsubstituted by one or more heteroatoms, in particular fluorine, and/orone or more groups including at least one heteroatom, in particularcarboxyl, sulfonyl and/or phosphonyl.

R₁₁ can in particular represent a —(CH₂)_(x)—R₁₃ group where x is aninteger comprised between 0 and 4 and R₁₃ represents a fluorine atom ora carboxyl, sulphonyl, phosphonyl, tetrazole or keto-oxadiazole group,in particular a tetrazole or keto-oxadiazole group of respectiveformulas:

In general formula (IX), R₉ and R₁₀, which are identical or different,may also each represent a group of general formula (XVIII′):

in which y′ is an integer comprised between 1 and 10 and R₁₈ is selectedfrom —F, —CO₂H, —SO₃H, —P(O)(OH)₂, —P(O)(OCH₃)₂, —P(O)(OCH₂CH₃)₂,—N(CH₃)₂, —N(CH₂—CH₃)₂,

where R₁₉ represents a hydrogen atom or a methyl group.

The compound used according to the invention may in particularcorrespond to the general formula (X):

in which Y₁′, Y₂′, R₄′, A₃, B₁, B₂, R₉, R₁₀, R₁₃ and x are as definedabove.

It can in particular correspond to the general formula (XI):

in which Y₁′, Y₂′, R₄′, A₃, B₁, R₉, R₁₀, R₁₃ and x are as defined above.

It can otherwise correspond to the general formula (XII):

in which Y₁′, Y₂′, R₄′, A₃, B₁, B₂, R₉, R₁₀, R₁₃ and x are as definedabove.

In particular embodiments of the invention, the used compoundcorresponds to the general formula (XIII):

in which Y₁′, R₄′, A₃, B₁, R₉, R₁₀, R₁₃ and x are as defined above.

In particular, it can correspond to the general formula (XIV):

in which Y₁′, R₄′, R₉, B₁, R₁₀, R₁₃ and x are as defined above.

In particular, it can correspond to the general formula (XV):

in which Y₁′, R₄′, R₉, B₁, R₁₀, R₁₃ and x are as defined above.

A particularly preferred sub-family of the general formula (XV) in thecontext of the invention corresponds to the general formula (XVI):

in which Y₁′, Y₂′, R₄′, R₁₃ and x are as defined above.

More generally, the present invention concerns a compound of formula (I)below, or one of its pharmaceutically acceptable salts, for its use, asan active agent, for said treatment of hemophilia in a subject sufferingfrom illness:

in which

W₁, W₂, W₃ and W₄, which are identical or different, each represent anoxygen atom or a bivalent radical selected from the groups —CH₂—,carbonyl —CO—, amine, in particular secondary amine —NH—, and sulphonyl—SO₂—,

R₁ and R₂, which are identical or different, each represent a hydrogenatom, a hydroxyl group or a linear, branched and/or cyclic, saturated orunsaturated, aromatic or not hydrocarbon radical, preferably C1-C8 andin particular C1-C4, which is optionally substituted, possiblycomprising one or more heteroatoms and/or one or more groups includingat least one heteroatom and possibly including a single cycle or severalcycles, where appropriate fused cycles,

R₃ represents a hydrogen atom, a halogen atom, an alkyl group,preferably C1-C8 and preferably C1-C4, or a hydroxyl group,

and R represents a hydrogen atom, a hydroxyl group, an —NH₂ group or alinear, branched and/or cyclic, saturated or unsaturated, aromatic ornot hydrocarbon radical, which is optionally substituted, which maycontain one or more heteroatoms and/or a or several groups including atleast one heteroatom and possibly comprising a single cycle or severalcycles, where appropriate fused cycles.

The compound used according to the invention is adamantane, ortricyclo[3.3.1.1(3.7)]decane, of chemical formula:

or one of its derivatives or analogues corresponding to the generalformula (I).

Any non-toxic conventional salt of the compound of general formula (I)can be used according to the invention, for example a metallic salt suchas a sodium, potassium, magnesium, calcium, lithium, etc. salt.Alternatively, a salt formed from organic or inorganic acids may beused, for example salts derived from inorganic acids such ashydrochloric, hydrobromic, phosphoric, sulfuric, etc. acids, and saltsderived from organic acids such as acetic, trifluoroacetic, propionic,maleic, benzoic, stearic, etc. acids. The salt can be synthesized,starting from the compound of general formula (I), according to anychemical method conventional in itself.

All the properties described in the present description for the compoundof general formula (I) are also applied to its pharmaceuticallyacceptable salts.

The general formula (I) above further encompasses all possiblecombinations of isomeric forms at the asymmetric carbons, and allmixtures of such isomeric forms. From a mixture of isomers, eachparticular isomer can be obtained by purification methods conventionalin themselves for those skilled in the art.

A particularly preferred isomer according to the invention correspondsto the general formula (I′):

In particular embodiments, the compound used according to the inventionmeets one or more of the characteristics below, implemented alone or inany technically relevant combination.

Preferably, at least one, preferably at least two, preferably at leastthree and preferably all four, among W₁, W₂, W₃ and W₄, represent(s) amethylene —CH₂— bridge.

R₁ and R₂, which are identical or different, also preferably eachrepresent a hydrogen atom, a hydroxyl group, a C1-C8 alkyl group,preferably a C1-C4 alkyl group or an optionally substituted phenylradical.

R₁ and R₂ can for example be identical, and each represent a hydrogenatom or a methyl group. They can otherwise be different, and for examplerepresent for one, a hydrogen atom, and for the other, a hydroxyl group.

Particular compounds according to the invention correspond to thefollowing combinations of characteristics:

-   -   W₁, W₂, W₃ and W₄ each represent a methylene bridge, R₃        represents a hydrogen atom, R₁ represents a hydrogen atom and R₂        represents a hydroxyl group;    -   W₁, W₂, W₃ and W₄ each represent a methylene bridge, R₃        represents a hydrogen atom and R₁ and R₂ each represent a methyl        group;    -   W₁, W₃ and W₄ each represent a methylene bridge, W₂ represents a        carbonyl group, R₃ represents a hydrogen atom, and R₁ and R₂        each represent a methyl group.

W₂ can alternatively represent a group of formula:

In this respect, the compound of general formula (I) can be bromantane,in which W₁, W₃ and W₄ each represent a methylene bridge —CH₂—, and R₁,R₂, R₃ and R each represent a hydrogen atom.

In particular embodiments of the invention, R₂ is selected from thegroups of chemical formulas:

The compound used according to the invention may thus in particular besaxagliptin, of chemical formula:

or vildagliptin, of the chemical formula:

In the general formula (I), R can represent a primary amine group.

The compound used according to the invention can then in particular beamantadine or memantine, in which W₁, W₂, W₃ and W₄ each represent amethylene —CH2— bridge, R₃ represents a hydrogen atom, and R₁ and R₂each represent a hydrogen atom for the first, and a methyl group for thesecond.

R may otherwise, for example, represent a group selected from thefollowing groups:

The compound used according to the invention can then in particular beadapromine, rimantadine or tromantadine, in which W₁, W₂, W₃ and W₄ eachrepresent a methylene —CH₂— bridge, and R₁, R₂ and R₃ each represent ahydrogen.

In particularly preferred embodiments of the invention, R represents agroup of formula —Y₁-A₁, in which:

Y₁ represents a covalent bond, an amine group or a linear or branched,saturated or unsaturated carbon radical, which is optionally interruptedand/or substituted by one or more heteroatoms and/or one or more groupsincluding at least one heteroatom, said carbon radical includingpreferably 1 to 4 carbon atoms, in particular an —NH—CO—, —CO—NH—,—NH—CS— or —CS—NH— group,

and A₁ represents a cyclic or heterocyclic, saturated or unsaturated,optionally substituted hydrocarbon, which may include a single ring,aromatic or not, or several fused rings, each of said rings possiblybeing aromatic or not.

The compound then corresponds to the general formula (II):

in which W₁, W₂, W₃, W₄, R₁, R₂, R₃, Y₁ and A₁ are as defined above.

A₁ can in particular be of the monocyclic, bicyclic or tricyclic type.

Preferably, A1 represents a monocyclic unit, preferably aromatic,including from 4 to 6 atoms, one or more of these atoms possibly being aheteroatom, and substituted on at least one, preferably at least two(this being understood in addition to the bond to Y₁), ring atoms.

A₁ may in particular represent a phenyl radical, substituted on at leasttwo of the ring atoms (this being understood in addition to the bond toY₁), the substituents preferably being located in the para position withrespect to each other, one of the substituents further preferably beinglocated in the ortho position relative to the bond Y₁.

Preferably, A₁ is substituted, in the position ortho to the bond to Y₁,by a group R₄ representing a hydrogen atom, a hydroxyl group, a halogenatom, an amine group or a linear, branched and/or cyclic, saturated orunsaturated, aromatic or not carbon radical, which is optionallyinterrupted and/or substituted by one or more heteroatoms and/or one ormore groups including at least one heteroatom.

In particularly preferred embodiments according to the invention, inparticular when A₁ represents an aromatic carbocyclic or heterocyclicgroup, in particular with 6 atoms, A₁ is substituted by at least onegroup of general formula (II′):

—Y₂-A₂   (II′)

in which

Y₂ represents a covalent bond, an amine group, or a linear or branched,saturated or unsaturated carbon radical, which is optionally interruptedand/or substituted by one or more heteroatoms and/or one or more groupsincluding at least one heteroatom, preferably C1-C4, in particular an—NH—CO—, —CO—NH—, —NH—CS— or —CS—NH— group,

and A₂ represents an optionally substituted cyclic or heterocyclicgroup, which may include a single ring, which may or may not bearomatic, or several fused rings, each of said rings may or may not bearomatic.

A₂ can in particular be of the monocyclic, bicyclic or tricyclic type.

Preferably, A₂ represents an optionally substituted cyclic orheterocyclic group including two fused rings, at least one of said ringsbeing aromatic, each of said rings preferably including between 4 and 6atoms, one or more of these atoms possibly being a heteroatom.

Preferably, in such a configuration, each of the rings of A₂ isaromatic. Each of the rings also preferably includes 6 carbon atoms.

A₂ is preferably substituted on at least one, preferably at least two,of the atoms of at least one ring. A₂ is preferably substituted on atleast one, preferably at least two, ring atoms not carrying the bond toY₂.

Preferably, A₂ represents a naphthalene unit, optionally substituted,and preferentially substituted on at least the ring not carrying thebond to Y₂.

In particular embodiments of the invention, A₂ is substituted by atleast one group selected from the group consisting of halogen atoms, inparticular chlorine, bromine or iodine atoms, hydroxyl, amine or amineoxide groups, and linear, branched and/or cyclic, saturated orunsaturated, aromatic or non-aromatic carbon radicals, which areoptionally interrupted and/or substituted by one or more heteroatomsand/or one or more groups including at least one heteroatom. As examplesof such radicals, mention may be made of the amide, ketoxime, carbonyl,carboxyl, ester, alkyl, in particular C1-C8, in particular C1-C4, aryl,etc. radicals.

In particular embodiments of the invention, the compound corresponds tothe general formula (III):

in which

W₁, W₂, W₃, W₄, R₁, R₂, R₃, Y₁, Y₂ and A₂ are as defined above,

and R₄ represents a hydrogen atom, a hydroxyl group, a halogen atom, anamine group or a linear, branched and/or cyclic, saturated orunsaturated, aromatic or non-aromatic carbon radical, which isoptionally interrupted and/or substituted by a or more heteroatomsand/or one or more groups including at least one heteroatom.

In particular, in the general formula (III), R₄ can represent a hydrogenatom or an —OR5 group, where R₅ represents a C1-C8, preferably C1-C4,alkyl group, and in particular a methyl group.

The compound used according to the invention may, for example,correspond to one of the general formulas (IIIa), (IIIb), (IIIc) or(IIId) below:

in which R₄, Y₂ and A₂ are as defined above.

In particularly preferred embodiments of the invention, the compoundcorresponds to the general formula (IV):

in which

W₁, W₂, W₃, W₄, R₁, R₂, R₃, Y₁ and Y₂ are as defined above,

R₅ represents a hydrogen atom or a C1-C8, preferably C1-C4 alkyl group,for example a methyl group,

and R₆ represents a halogen atom, in particular a chlorine, bromine andiodine atom, a hydroxyl, amine or amine oxide group, or a linear,branched and/or cyclic, saturated or unsaturated, aromatic or not carbonradical, which is optionally interrupted and/or substituted by one ormore heteroatoms and/or one or more groups including at least oneheteroatom.

R₆ can for example represent an amide, ketoxime, carbonyl, carboxyl,ester, in particular C1-C8, in particular C1-C4 alkyl, aryl, etc.radical.

In particular embodiments of the invention, R₆ represents a —CO—OR₇group, where R₇ represents a hydrogen atom, a C1-C8, preferably C1-C4,alkyl group, an aryl group or a C6-C14 arylalkyl group.

The compound used according to the invention may in particularcorrespond to one of the general formulas (IVa), (IVb), (IVc) and (IVd)below:

in which W₁, W₂, W₃, W₄, R₁, R₂, R₃, R₅ and R₆ are as defined above

A particularly preferred compound according to the invention isadapalene, name given to6-[3-(1-adamantyl)-4-methoxyphenyl]naphthalene-2-carboxylic acid, offormula (V):

Adapalene is particularly effective in restoring coagulation in theplasma of patients with severe hemophilia A.

Other particularly preferred compounds according to the invention,corresponding in particular to the general formula (III′), have theformulas (XVII) and (XIX):

Other compounds which can be used in accordance with the invention,corresponding in particular to the general formula (III′), have theformulas (XX), (XXI), (XXII) and (XXIII):

Other examples of compounds which can be used according to the inventionhave the formulas (VI), (VII) and (VIII) below:

The compound according to the invention can be administered to thesubject in need thereof, that is to say suffering from hemophilia, in atherapeutically effective amount, by any route, in particular by theenteral route, in particular oral, buccal or rectal, parenterally, inparticular subcutaneous, intramuscular, intravenous, intradermal, etc.The administration of the compound to the treated subject is preferablycarried out by oral route.

The term «therapeutically effective amount» means the amount of thecompound which makes it possible, when it is administered to thesubject, to obtain the desired level of therapeutic response, inparticular, for the particular case of hemophilia, the level ofrestoration of the desired clotting. The therapeutically effective doselevel of each specific compound for a particular subject variesdepending on many factors such as, for example, the exact pathology andits severity, body weight, age and general health of the subject,duration of treatment, any drugs used in parallel, the sensitivity ofthe individual to be treated, etc. Accordingly, the optimal dosage isdetermined by the doctor based on the parameters that he considersrelevant. The administration dosage of the compound used according tothe invention can for example be taken once or twice a day.

In preferred embodiments of the invention, the compound is contained ina pharmaceutical composition, within which it constitutes an activeprinciple, and is contained in a pharmaceutically acceptable vehicle.

This pharmaceutical composition may be in any form suitable for enteralor parenteral administration. It is preferably presented in a formsuitable for administration to the subject by the oral route.

All of the constituents of this pharmaceutical composition are of courseselected to be pharmaceutically compatible, that is to say that they donot produce any adverse, allergic or other undesirable reaction whenthey are administered to the subject, in particular to a mammal and inparticular to a human.

The pharmaceutical composition may contain any conventional excipient byitself. Such an excipient can be a diluent, an adjuvant or any otherconventional substance in itself for the constitution of medicaments,such as a preservative, filler, disintegrating, wetting, emulsifying,dispersing, antibacterial or antifungal agent, etc., or any mixturethereof

It may further contain one or more other active ingredients, acting ornot in synergy with the compound used according to the invention,

The pharmaceutical composition can be formulated according to anypharmaceutical form suitable for oral administration in mammals, and inparticular in humans. It may in particular be in the form of a powder,of tablets, of capsules, of granules, of a syrup, or of an oral solutionor suspension, prepared in a conventional manner by itself.

It is preferably packaged in the form of unit doses, each dosecontaining a therapeutically effective amount of the compound accordingto the invention. The concentration of the compound in each dose of thepharmaceutical composition is thus preferably selected to deliver to thesubject, at each administration, an amount of compound which iseffective to obtain the desired therapeutic response. The pharmaceuticalcomposition is for example packaged in the form of unit doses, each mayin particular comprise an amount comprised between 1 and 10 g of thecompound according to the invention.

The present invention is also expressed in terms of a method fortreating hemophilia in a subject, and in particular a method forrestoring coagulation in the plasma of a subject afflicted withhemophilia. The subject can in particular be a mammal, andpreferentially a human being. This method comprises the administration,to said subject in need, of a therapeutically effective amount of thecompound as defined above, or one of its pharmaceutically acceptablesalts. This method can meet one or more of the characteristics describedabove with reference to the use of the compound according to theinvention for the treatment of hemophilia.

The present invention is also expressed in terms of the use of acompound according to the invention, or of one of its pharmaceuticallyacceptable salts, for the manufacture of a medicament for the treatmentof hemophilia. This use may correspond to one or more of thecharacteristics described above with reference to the use of thecompound according to the invention for the treatment of hemophilia.

The characteristics and advantages of the invention will appear moreclearly in the light of the examples of implementation below, providedpurely by way of illustration and in no way limiting of the invention,with the assistance of FIGS. 1 to 4 , in which:

FIG. 1 shows a graph representing the results (amount of thrombin as afunction of time) of an ex vivo thrombin generation test for the plasmaof a subject suffering from severe hemophilia A, in the presence ofplasma factor FVIII (100% VIII, positive control), dilution buffer (0%VIII, negative control), and a compound according to the invention,adapalene, at respective concentrations of 0.5 μM, 5 μM and 50 μM.

FIG. 2 represents the chemical structure of comparative compounds C1 toC9 implemented in an example, not corresponding to the general formula(I).

FIG. 3 shows a histogram representing the amount of thrombin measured atthe peak during an ex vivo thrombin generation test (TGT) in the plasmaof an individual suffering from severe hemophilia A, in the presence ofplasma factor FVIII (100% VIII, positive control), dilution buffer (0%VIII, negative control) and in the presence of adapalene at 50 μM (Ad)or of a comparative compound C1 to C9 not corresponding to the generalformula (I).

FIG. 4 shows a histogram representing the total amount of thrombingenerated (endogenous thrombin potential) during an ex vivo thrombingeneration test (TGT) in the plasma of an individual with severehemophilia A, in the presence of plasma FVIII factor (100% VIII,positive control), dilution buffer (0% VIII, negative control) and inthe presence of adapalene at 50 μM (Ad) or a comparative compound C1 toC9 not corresponding to the general formula (I).

Example 1—Ex Vivo Thrombin Generation Test

When coagulation is activated, a chain of enzymatic reactions, calledthe coagulation cascade, occurs. It results in the production ofthrombin (factor IIa), the last enzymatic «link» in this coagulationcascade.

The thrombin generation test consists of measuring the kinetics ofappearance of this key coagulation factor in the plasma over time. Afteractivation of coagulation by calcium, the amount of thrombin changesover time. It is measured using a synthetic thrombin substrate coupledto a fluorescent molecule (ZGGR-AMC). The main parameters determined arethe latency time before observing an increase in thrombin generation,the thrombin peak corresponding to the maximum amount of thrombingenerated and the ETP (endogenous thrombin potential) corresponding tothe total amount of thrombin generated in plasma during the test. In thecase of a patient with hemophilia A, the generation of thrombin is lowor even almost zero for some patients. Adding the missing coagulationfactor (factor VIII) to its physiological level (1 Ul/mL or 100%)restores coagulation in patients and recovers a «normal» thrombingeneration. Thus, the thrombin generation test makes it possible toglobally evaluate the coagulation rate of a given plasma and in thepresent case, it makes it possible to evaluate the capacity of amolecule to restore or not restore coagulation in a hemophiliac patient.

For this example, several ex vivo thrombin generation tests were carriedout on plasma from a patient suffering from severe hemophilia A,therefore devoid of factor FVIII, in order to evaluate the effect oncoagulation of a compound of general formula (I), more particularlyadapalene, of formula (V) above, on the kinetics and the generatedamount of thrombin.

Hemophiliac patient plasma was obtained from Cryopep company(Montpellier, France).

Adapalene is commercially available, in particular from Prestwickcompany. It was dissolved in an 8% dimethylsulfoxide (DMSO) solutionthen diluted to a concentration of 1 mM and then tested at the followingconcentrations: 50 μM, 5 μM, 0.5 μM (final concentrations in plasma).

The thrombin generation test was performed at 37° C. using a fullyautomated STA-Genesia analyzer (Diagnostica Stago) with STG®-Bleedscreenreagent (Diagnostica Stago) according to the manufacturer's instructionsand according to the method established by Pr. Hemker in 2003. TheSTG®-Bleedscreen reagent is a mixture of tissue factor (TF) at lowconcentration with phospholipid vesicles (PL). The test is triggered bythe addition of a mixture of calcium+fluorescent substrate (ZGGR-AMC)(STG®-FluoStart mixture).

From a technical point of view, 4 volumes of surcharged plasma sampleare added to 1 volume of «initiator complex» (STG®-Bleedscreen) andincubated for 10 min at 37° C. Then, the reaction is triggered by adding1 volume of STG®-FluoStart (mixture of CaCl₂ and ZGGR-AMC substrate) andthe fluorescence signal is measured over time. Each test is performed induplicate

For each tested molecule, 475 μL of plasma from the hemophiliac patientwere surcharged with 25 μL of a solution containing different amounts ofcompound (molecule to be tested, factor VIII or dilution buffer) toobtain the desired final concentration (systematic dilution of themolecule to be tested in the plasma at 1/20). For example, to obtain thefinal concentration of 50 μM in plasma, 25 μL of a 1 mM solution wasadded to 475 μL of plasma. The preparation of 500 μL of surchargedplasma allows to perform the 2 thrombin generation tests (duplicate),the 2 calibration tests (duplicate) and takes into account the deadvolume of the automaton.

In parallel with the tests on the different chemical compounds, theplasma of a hemophiliac patient is surcharged with the same buffer fordiluting the compound, an 8% solution of dimethylsulfoxide (DMSO), as anegative control (0.4% of final DMSO) in order to obtain the basal levelof thrombin generation of the used plasma. The positive control is thesame plasma surcharged with plasma factor VIII (Factane, LFB, France) ata concentration of 1 IU/mL (or 100% factor VIII) in order to obtain theexpected «normal» level of used thrombin generation plasma.

The results obtained in thrombin generation, for each of the testedadapalene concentrations, are shown in FIG. 1 .

The negative control (plasma from a hemophiliac A patient surchargedwith the dilution buffer) shows weak thrombin generation with a peak at25 nM of thrombin and an ETP at 360 nM·min. The positive control (plasmafrom a hemophiliac A patient surcharged with 1 IU/mL of factor VIII)shows a «normal» generation of thrombin with a peak at 51 nM and an ETPat 599 nM·min. For the different concentrations of adapalene, anincrease in the generation of thrombin is observed depending on theconcentration of adapalene: the higher the concentration, the greaterthe generation of thrombin. At 0.5 μM, adapalene already has an effecton increasing thrombin generation with a peak at 29.7 nM and an ETP at455 nM·min. At 5 μM, the increase in thrombin generation is greater witha peak at 39 nM and an ETP at 504 nM·min. At the concentration of 50 μM,adapalene restores the generation of thrombin to the same level as thepositive control (100% FVIII) with a peak at 55 nM and an ETP at 588nM·min.

By way of comparison, several compounds with a close structure, but notcorresponding to the general formula (I) (compounds C1 to C9), were alsosubjected to the same test. These compounds are shown in FIG. 2 . Eachof these compounds was surcharged into the plasma of the hemophiliacpatient under the same conditions as adapalene, to the tune of 50 μM.

The results obtained, for adapalene (Ad) at 50 μM and for thecomparative compounds C1 to C9, are shown in FIG. 3 and FIG. 4 .

It is observed that among the various tested compounds, only adapalene(Ad) at 50 μM makes it possible to obtain an increase in the generationof thrombin compared to the negative control, with a peak of generatedthrombin and an ETP at the same level as the positive control.

Example 2—Effect on FXa Inhibition by TFPI

The ability of adapalene to reverse FXa inhibition by TFPI was assessedby using a low TFPI concentration FXa activity assay. For this test, atruncated human TFPI (TFPI-K1K2) was used, which is common to both TFPIisoforms α and β, having the amino acid sequence SEQ ID No 1:

DSEEDEEHTIITDTELPPLKLMHSGCAFKADDGPCKAIMKRFFFNIFTRQCEEFIYGGCEGNQNRFESLEECKKMCTRDNANRIIKTTLQQEKPDFCFLEEDPGICRGYITRYFYNNQTKQCERFKYGGCLGNMNNFETLEECKNIC EDGPNGF.

Adapalene was tested for its ability to release FXa inhibition byTFPI-K1K2 using a colorimetric assay in a 96-well plate format. Allsteps were performed at room temperature. FXa inhibition by increasingTFPI-K1K2 concentrations was first analyzed to determine the bestdetection conditions. Concentrations of TFPI-K1K2 and FXa (New EnglandBiolabs) of 30 nM and 0.5 nM, respectively, were selected to ensurecomplete inhibition of FXa, without a significant excess of TFPI-K1K2.Each protein was diluted using the same buffer: 20 mM Hepes, 135 mMNaCl, 1% BSA, 2 mM CaCl2, pH 7.3. The test was performed manually in96-well plates (Nunc Maxisorp®). The experiment was performed induplicate at a final adapalene concentration of 50 μM.

Briefly, 14.5 μL of 350 μM adapalene, prediluted in the buffer describedabove, was added to 62.5 μL 50 nM TFPI-K1K2 and mixed together byaspiration/dispensing. After 10 min of incubation at room temperature,6.25 μL of 8 nM FXa was added, the mixture was mixed again, and theactivity of uninhibited FXa was quantified by the addition of 18 μL ofPNAPEP-1025 (Cryopep), an FXa substrate, diluted to 2 mM in H₂O.

For the negative control, 14.5 μl of 0.25% DMSO was added to 62.5 μl ofTFPI-K1K2, and for the positive control, 14.5 μl of 0.25% DMSO was addedto 62, 5 μl of buffer. Then, after 10 min of incubation at roomtemperature, 6.25 μl of 8 nM FXa and 18 μl of PNAPEP-1025 were added aspreviously described.

The plates were centrifuged to remove any bubbles and the opticaldensity (OD) at 405 nm, corresponding to the hydrolysis of thePNAPEP-1025 substrate, was measured for 1 h at room temperature. Theabsorbance value at t0, corresponding to an absorbance of 0.05, wassubtracted and the thrombin generation restoration value was reported asa percentage of the positive control.

The following results were obtained: negative control: OD=0.048;positive control: OD=0.406; adapalene at 50 μM: OD=0.105. The measuredcoagulation restoration percentage is approximately 14%. This resultdemonstrates that adapalene exhibits an inhibition lifting effect of FXaby TFPI.

Example 3—Synthesis of Compounds According to the Invention Compound H27

The compound H27 (HEMO-027) of formula:

is prepared according to the following reaction scheme:

Methyl2-(3-(adamantan-1-yl)-4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate(7)

Pd₂(dba)₂ (1.7 mg, 0.0016 mmol, 1 mol %) was added to a flame-driedreactor followed by SPHOS (2.6 mg, 0.0064 mmol, 4 mol %),1-(5-bromo-2-methoxyphenyl)adamantane (5) (50 mg, 0.16 mmol, 1 eq.),methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylate hydrochloride (6)(43 mg , 0.19 mmol, 1.2 eq.) and NaOtBu (36.5 mg, 0.38 mmol, 2.4 eq.).Anhydrous toluene (600 μl, 267 mM) was added and the reactor was sealed.The resulting mixture was stirred at 100° C. for 16 h. After reachingroom temperature, H₂O and AcOEt were added. The aqueous phase wasextracted 3 times with AcOEt, and the combined organic phases wereevaporated over MgSO₄, filtered and concentrated in vacuo. The residuewas eluted on a column of silica gel with 4:1 cyclohexane-AcOEt toobtain (7) (66 mg, 96%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ7.85; (s, 1H, H-ar), 7.84; (d, 1H, J=7.9 Hz, H-ar), 7.20; (d, 1H, J=7.9Hz, H- ar), 6.99; (s, 1H, H-ar), 6.85-6.80; (m, 2H, 2 H-ar), 4.32; (s,2H, NCH₂), 3.91; (s, 3H, OCH₃), 3.81; (s, 3H, OCH₃), 3.45; (t, 2H, J=5.8Hz, NCH₂CH₂), 3.05; (t, 2H, J=5.8 Hz, NCH₂CH₂), 2.11; (db, 6H), 2.07;(db, 3H), 1.78; (db, 6H). 13C NMR (CDCL₃, 100.6 MHz) δ 167.3, 153.5,145.0, 140.4, 139.6, 135.0, 130.2, 128.3, 127.1, 126.8, 117.4, 114.7,112.7, 55.6, 53.4, 52.1, 48.8, 40.8, 29.3.

2-(3-(adamantan-1-yl)-4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-6carboxylic acid (HEMO-027)

To a solution of (7) (22 mg, 0.051 mmol) in 2:1 THF:H₂O (2 mL) at roomtemperature was added LiOH (3.5 mg, 0.13 mmol, 2.5 eq.). After stirringfor 16 h, 1M HCl was added to reach a pH=1. The precipitate formed wasfiltered and washed with H₂O then with cold MeOH. The resulting solidwas dried in vacuo to obtain (HEMO-027) (8 mg, 38%) as a light yellowsolid. ¹H NMR (DMSO-d₆, 400 MHz): d 12.79; (bs, 1H, OH), 7.75; (s, 1H,H-ar), 7.73; (d, 1H, J=8.0 Hz, H-ar), 7.32; (d, 1H, J=8.0 Hz, H-ar),6.88-6.81; (m, 3H, 3 H-ar), 4.29; (s, 2H, NCH₂), 3.73; (s, 3H, OCH₃),3.39; (t, 2H, J=5.8 Hz, NCH₂CH₂), 2.97; (t, 2H, J=5.8 Hz, NCH₂CH₂),2.04; (bs, 9H), 1.73; (bs, 6H). ¹³C NMR (DMSO-d₆, 125.7 MHz) d 167.3,152.3, 144.5, 140.0, 138.2, 134.7, 130.2, 129.6, 128.6, 126.9, 126.6,115.6, 114.2, 113.0, 55.6, 51.9, 47.5, 36.6, 28.5, 28.4. HRMS(ESI/Q-TDE) m/z calc. for C₂₇H₃₁NO₃ [M+H]⁺ 418.2377, obtained 418.2369.

Compound H31

The compound H31 (HEMO-031) of formula:

is prepared according to the following reaction scheme:

Methyl 6-(3-(adamantan-1-yl)-4-methoxyphenyl)quinoline-2-carboxylate(10)

Pd(OAc)₂ (6.10 mg, 0.027 mmol, 5 mol %) and S-Phos (11.2 mg, 0.027 mmol,5 mol %) were added to a degassed solution of methyl6-bromoquinoline-2-carboxylate (8) (144.5 mg, 0.54 mmol, 1 eq.), boronicester (9) (200 mg, 0.54 mmol, 1 eq.) and Na₂CO₃ (173 mg, 1.63 mmol, 3eq.) in 10:1 Dioxane:H₂O. The obtained yellow suspension was stirred at80° C. for 16 h. H₂O was then added and the aqueous phase was extracted3 times with AcOEt. The combined organic phases were dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was eluted on a silicagel column with 0 to 70% AcOEt in Cyclohexane to obtain (10) (95 mg,41%) as a white solid. ¹H NMR (CDCl₃, 400 MHz): d 8.46; (d, 1H, J=8.9Hz, H-ar), 8.34; (d, 1H, J=8.5 Hz, H-ar), 8.17; (d, 1H, J=8.5 Hz, H-ar),8.03; (dd, 1H, J=2.1 Hz, J=8.9 Hz, H-ar), 7.95; (d, 1H, J=2.1 Hz, H-ar),7.54; (d, 1H, J=2.4 Hz, H-ar), 8.03; (dd, 1H, J=2.4 Hz, J=8.4 Hz, H-ar),6.94; (d, 1H, J=8.5 Hz, H-ar), 4.05; (s, 3H, CH₃), 3.85; (s, 3H, CH₃),2.11; (bs, 6H), 2.04; (bs, 3H), 1.74; (bs, 6H).

6-(3-(adamantan-1-yl)-4-m2thoxyph2nyl)quinoline-2-carboxylic acid(HEMO-031)

To a solution of ester (10) (30 mg, 0.07 mmol, 1 eq.) in 4:1 THF:MeOH atroom temperature was added 2M NaOH (105 μl, 0.21 mmol, 3 eq.). Theobtained solution was mixed for 16 h at 60° C. The reaction mixture wasthen poured into water and the aqueous phase was extracted with AcOEt.The resulting aqueous phase was acidified using 1M HCl and extracted 3times with AcOEt. The combined organic phases were dried over Na₂SO₄,filtered and concentrated in vacuo to obtain (HEMO-031) (17 mg, 59%) asa white solid. ¹H NMR (DMSO-d₆, 500 MHz): □ 8.57; (d, 1H, J=8.6 Hz,H-ar), 8.30; (d, 1H, J=1.4 Hz, H-ar), 8.19; (d, 1H, J=8.9 Hz, H-ar),8.15; (dd, 1H, J=1.9 Hz, J=9.0 Hz, H-ar), 8.11; (d, 1H, J=8.5 Hz, H-ar),7.69; (dd, 1H, J=2.2 Hz, J=8.4 Hz, H-ar), 7.61; (d, 1H, J=2.2 Hz, H-ar),7.14; (d, 1H, J=8.6 Hz, H-ar), 3.88; (s, 3H, CH₃), 2.14; (bs, 6H), 2.08;(bs, 3H), 1.77; (bs, 6H). ¹³C NMR (DMSO-d₆, 125.7 MHz) □ 166.5, 158.8,145.8, 140.0, 138.1, 137.4, 130.9, 130.1, 129.5, 129.2, 125.9, 125.2,124.0, 121.1, 112.8, 55.4, 36.6, 36.5, 28.4. HRMS (ESI/Q-TDE) m/z calc.for C₂₇H₂₈NO₃ [M+H]⁺ 414.2064, obtained 414.2060.

Compound H32

The compound H32 (HEMO-032) of formula:

is prepared according to the following reaction scheme:

Methyl 7-(3-(adamantan-1-yl)-4-methoxyphenyl)quinoline-3-carboxylate(12)

Pd(OAc)₂ (16.9 mg, 0.075 mmol, 10 mol %) and S-Phos (15.4 mg, 0.037mmol, 5 mol %) were added to a degassed solution of methyl7-bromoquinoline-3-carboxylate (11) (200 mg, 0.75 mmol, 1 eq.), boronicester (9) (415 mg, 1.13 mmol, 1.5 eq.) and Na₂CO₃ (239 mg, 02.25 mmol, 3eq.) in 10:1 Dioxane:H₂O. The obtained yellow suspension was stirred at80° C. for 16 h. H₂O was then added and the aqueous phase was extracted3 times with AcOEt. The combined organic phases were dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was eluted on a silicagel column with 0 to 70% AcOEt in Cyclohexane to obtain (12) (40 mg,13%) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz): □ 9.33; (d, 1H, J=2.2Hz, H-ar), 9.02; (d, 1H, J=2.2 Hz, H-ar), 8.28-8.26; (m, 2H, 2 H-ar),8.05; (dd, 1H, J=1.8 Hz, J=8.7 Hz, H-ar), 7.74; (dd, 1H, J=2.3 Hz, J=8.5Hz, H-ar), 7.63; (d, 1H, J=2.4 Hz, H-ar), 7.16; (d, 1H, J=8.6 Hz, H-ar),3.97; (s, 3H, CH₃), 3.89; (s, 3H, CH₃), 2.16; (bs, 6H), 2.08; (bs, 3H),1.77; (bs, 6H).

7-(3-(adamantan-1-yl)-4-methoxyphenyl)quinoline-3-carboxylic acid(HEMO-032)

To a solution of ester (12) (15 mg, 0.035 mmol, 1 eq.) in 2:1 THF:MeOHat room temperature, was added 2M NaOH (53 μl, 0.11 mmol, 3 eq.). Thesolution obtained was stirred for 2 hours at 60° C. The reaction mixturewas poured into water and the aqueous phase was extracted with AcOEt.The resulting aqueous phase was acidified with 1M HCl and extracted 3times with AcOEt. The combined organic phases were dried over Na₂SO₄,filtered and concentrated in vacuo to obtain (HEMO-032) (9 mg, 62%) as awhite solid. ¹H NMR (DMSO-d₆, 500 MHz): □ 13.45; (s, 1H, OH), 9.31; (d,1H, J=2.1 Hz, H-ar), 8.96; (d, 1H, J=1.8 Hz, H-ar), 8.25; (s, 1H, H-ar),8.23; (d, 1H, J=8.6 Hz, H-ar), 8.02; (dd, 1H, J=1.7 Hz, J=8.5 Hz, H-ar),7.73; (dd, 1H, J=2.2 Hz, J=8.5 Hz, H-ar), 7.61; (d, 1H, J=2.3 Hz, H-ar),7.14; (d, 1H, J=8.6 Hz, H-ar), 3.88; (s, 3H, CH₃), 2.14; (bs, 6H), 2.07;(bs, 3H), 1.76; (bs, 6H). ¹³C NMR (DMSO-d₆, 125.7 MHz) □ 166.4, 159.0,150.3, 149.7, 143.9, 138.2, 138.1, 130.8, 130.1, 126.6, 126.1, 125.3,124.8, 123.1, 112.8, 55.4, 36.6, 36.5, 28.4. HRMS (ESI/Q-TDE) m/z calc.C₂₇H₂₈NO₃ [M+H]⁺ 414.2064, obtained 414.2058.

Compound H35

The compound H35 (HEMO-035) of formula:

is prepared according to the following reaction scheme:

Methyl6-(3-(adamantan-1-yl)-4-((2-methoxyethoxy)methoxy)phenyl)-2-naphthoate(15)

Boronic acid (14) (500 mg, 1.39 mmol, 1 eq.) was added to theflame-dried reactor followed by methyl 6-bromo-2-naphthoate (13) (368mg, 1.39 mmol, 1 eq.), Pd(PPh₃)₄ (80 mg, 0.070 mmol, 5 mol %), and K₂CO₃(383 mg, 2.78 mmol, 2 eq.). After addition of 10:1 MeOH:H₂O (11.5 mL,120 mM) the reactor was then sealed. The solution obtained was stirredat 80° C. for 4 hours. After reaching room temperature, H₂O and CH₂Cl₂were added. The aqueous phase was extracted 3 times with CH₂Cl₂, and thecombined organic phases were washed with saturated NaCl solution, driedover MgSO₄, filtered and concentrated in vacuo. The residue was elutedon a column of silica gel containing 0 to 5% AcOEt in toluene to obtain(15) (610 mg, 88%) in the form of a white solid. ¹H NMR (CDCl₃, 400MHz): □ 8.61; (s, 1H, H-ar), 8.07; (dd, 1H, J=1.4 Hz, J=8.6 Hz, H-ar),8.01; (s, 1H, H-ar), 7.99; (d, 1H, J=8.6 Hz, H-ar), 7.92; (d, 1H, J=8.6Hz, H-ar), 7.79; (dd, 1H, J=1.6 Hz, J=8.5 Hz, H-ar), 7.92; (d, 1H, J=2.2Hz, H-ar), 7.51; (dd, 1H, J=2.2 Hz, J=8.5 Hz, H-ar), 7.29; (d, 1H, J=8.6Hz, H-ar), 5.39; (s, 2H, OCH₂O), 3.99; (s, 3H, OCH₃), 3.90; (dd, 1H,J=3.9 Hz, J=5.4 Hz, OCH₂), 3.62; (dd, 1H, J=3.9 Hz, J=5.4 Hz, OCH₂),3.42; (s, 3H, OCH₃), 2.20; (s, 6H), 2.11; (s, 3H), 1.81; (s, 6H). ¹³CNMR (CDCl₃, 100.6 MHz) □ 167.4, 156.7, 141.4, 139.1, 136.0, 133.8,131.4, 130.9, 129.8, 128.4, 127.1, 126.6, 126.2, 126.0, 125.7, 125.0,115.2, 93.5, 71.7, 68.0, 59.2, 52.3, 40.9, 37.4, 37.2, 29.2. HRMS(ESI/Q-TDE) m/z calc. pour C₃₂H₄₀NO₅ [M+NH₄]⁺ 518.2901, obtained518.2890.

Methyl 6-(3-(adamantan-1-yl)-4-hydroxyphenyl)-2-naphthoate (16)

A suspension of (15) (610 mg, 1.22 mmol, 1 eq.) in HCl (2M in Et₂O, 25mL) was stirred at room temperature for 16 h. A saturated solution ofNaHCO₃ was added and the aqueous phase was extracted 3 times with AcOEt.The combined organic phases were washed with saturated NaCl solution,dried over MgSO₄, filtered and concentrated in vacuo. The residue waseluted on a silica gel column with 0 to 40% AcOEt in hexane to obtain(16) (440 mg, 87%) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz): □ 9.58;(s, 1H, OH), 8.61; (s, 1H, H-ar), 8.17; (s, 1H, H-ar), 8.14; (d, 1H,J=8.6 Hz, H-ar), 8.06; (d, 1H, J=8.7 Hz, H-ar), 7.97; (dd, 1H, J=1.1 Hz,J=8.6 Hz, H-ar), 7.86; (dd, 1H, J=0.9 Hz, J=8.6 Hz, H-ar), 7.52-7.48;(m, 2H, 2 H-ar), 6.92; (d, 1H, J=8.2 Hz, H-ar), 3.91; (s, 3H, OCH₃),2.17; (s, 6H), 2.06; (s, 3H), 1.75; (s, 6H). ¹³C NMR (DMSO-d₆, 100.6MHz) □ 166.4, 156.5, 140.9, 136.1, 135.6, 130.7, 130.2, 129.9, 129.8,128.5, 126.0, 125.4, 125.2, 125.0, 123.6, 117.0, 52.1, 36.6, 36.4, 28.4.

Methyl 6-(3-(adamantan-1-yl)-4-(prop-2-yn-1-yloxy)phenyl)-2-naphthoate(17)

To a solution of naphthoate (16) (100 mg, 0.24 mmol, 1 eq.) in anhydrousTHF (2.4 ml, 0.1 M) under an argon atmosphere at 0° C. in a flask driedby flame was added NaH (60%, 12 mg, 0.29 mmol, 1.2 eq.). The obtainedmixture was stirred for 5 min at 0° C. then propargyl bromide (33 μl,0.29 mmol, 1.2 eq.) was then added. The solution, after reaching roomtemperature, was mixed for 3 hours. H₂O was added and the aqueous phasewas extracted 3 times with CH₂Cl₂ and the combined organic phases werewashed with saturated NaCl solution, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was eluted on a silica gel columnwith 5:95 AcOEt:Cyclohexane to obtain (17) (102 mg, 94%) as a whitesolid. ¹H NMR (CDCl₃, 400 MHz): □ 8.62; (s, 1H, H-ar), 8.07; (dd, 1H,J=1.6 Hz, J=8.6 Hz, H-ar), 8.01; (s, 1H, H-ar), 7.99; (d, 1H, J=8.6 Hz,H-ar), 7.92; (d, 1H, J=8.6 Hz, H-ar), 7.79; (dd, 1H, J=1.7 Hz, J=8.5 Hz,H-ar), 7.62; (d, 1H, J=2.3 Hz, H-ar), 7.54; (dd, 1H, J=2.3 Hz, J=8.4 Hz,H-ar), 2.55; (t, 1H, J=2.3 Hz, CHCCH₂), 2.20; (s, 6H), 2.12; (s, 3H),1.81; (s, 6H). ¹³C NMR (CDCl₃, 100.6 MHz) □ 167.4, 157.0, 141.4, 139.6,136.1, 133.7, 131.5, 131.0, 129.9, 128.4, 127.2, 126.6, 126.4, 125.8,125.7, 125.0, 113.5, 78.9, 75.5, 55.9, 52.3, 40.9, 37.4, 37.2, 29.2.

6-(3-(adamantan-1-yl)-4-(prop-2-yn-1-yloxy)phenyl)-2-naphthoic acid (HEMO-035)

To a solution of (17) (100 mg, 0.22 mmol) in 2:1 THF:H2O (3 mL) at roomtemperature was added LiOH (13 mg, 0.55 mmol, 2.5 eq.). After mixing for16 h, 1M HCl was added to reach pH=1. The formed precipitate wasfiltered, washed with H₂O and dried in vacuo to obtain (HEMO-035) (36mg, 38%) as a white solid. ¹H NMR (DMSO-d₆, 500 MHz): □ 13.03; (s, 1H,OH), 8.62; (s, 1H, H-ar), 8.23; (s, 1H, H-ar), 8.16; (d, 1H, J=8.6 Hz,H-ar), 8.08; (s, 1H, H-ar), 7.98; (d, 1H, J=8.6 Hz, H-ar), 7.90; (d, 1H,J=8.6 Hz, H-ar), 7.66; (dd, 1H, J=1.3 Hz, J=8.4 Hz, H-ar), 7.60; (s, 1H,H-ar), 7.18 (d, 1H, 8.5 Hz, H-ar), 4.91 (d, J =1.6 Hz, H-ar), 3.60 (t,1H, J =1.6 Hz, CHCCH₂), 2.16; (s, 6H), 2.08; (s, 3H), 1.77; (s, 6H). ¹³CNMR (DMSO-d₆, 125.7 MHz) □ 167.5, 156.5, 140.1, 138.5, 135.5, 132.3,131.0, 130.3, 129.8, 128.4, 127.7, 126.0, 125.6, 125.5, 125.3, 124.3,114.0, 79.3, 78.1, 67.0, 56.6, 40.1, 36.6, 36.5, 28.4. HRMS (ESI/Q-TDE)m/z calc. for C₃₀H₂₇O₃ [M−H]⁻ 435.1966, obtained 435.1962.

Compound H38

The compound H38 (HEMO-038) of formula:

is prepared according to the following reaction scheme:

Ethyl 6-(3-(adamantan-1-yl)-4-methoxyphenyl)-4-hydroxy-2-naphthoate (19)

Boronic acid (2) (150 mg, 0.53 mmol, 1 eq.) was added to a flame-driedreactor followed by bromoester (18) (179 mg, 0.53 mmol, 1 eq.),Pd(PPh₃)₄ (31 mg, 0.027 mmol, 5 mol %), and K₂CO₃ (146 mg, 1.06 mmol, 2eq.). 10:1 EtOH:H₂O (4.4 mL, 120 mM) was added and the reactor wassealed. The resulting mixture was stirred at 80° C. for 5 hours. Afterreaching room temperature, H₂O and CH₂Cl₂ were added. The aqueous phasewas extracted 3 times with CH₂Cl₂, and the combined organic phases werewashed with saturated NaCl solution, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was triturated in cold CH₂Cl₂ and theresulting precipitate was filtered and dried in vacuo to obtain (19)(142 mg, 59%) as a white solid. ¹H NMR (DMSO-d₆, 500 MHz): □ 10.55; (s,1H, OH), 8.31; (s, 1H, H-ar), 8.08; (s, 1H, H-ar), 8.06; (d, 2H, J=8.4Hz, H-ar), 7.85; (d, 1H, J=8.4 Hz, H-ar), 7.60; (d, 1H, J=8.1 Hz, H-ar),7.53; (s, 1H, H-ar), 7.41; (s, 1H, H-ar), 7.10; (d, 1H, J=8.4 Hz, H-ar),4.35; (q, 2H, J=6.9 Hz, OCH₂), 3.85; (s, 3H, OCH₃), 2.12; (bs, 6H),2.05; (bs, 3H), 1.74; (bs, 6H), 4.35; (t, 2H, J=7.1 Hz, CH₃). ¹³C NMR(DMSO-d₆, 125.7 MHz) □ 166.0, 158.5, 153.5, 139.3, 138.0, 132.2, 131.9,129.8, 127.2, 127.1, 126.2, 125.6, 124.9, 121.0, 118.3, 112.8, 106.9,60.7, 55.3, 40.1, 36.6, 36.5, 28.4, 14.3.

6-(3-(adamantan-1-yl)-4-methoxyphenyl)-4-hydroxy-2-naphthoic acid(HEMO-038)

To a suspension of ester (19) (25 mg, 0.055 mmol) in 2:1 THF:H₂O (1.5mL) was added LiOH (3 mg, 0.11 mmol, 2.5 eq.). After mixing for 4 h at60° C., 1M HCl was added to reach pH=1. The obtained precipitate wasfiltered, washed with H₂O and dried in vacuo to obtain (HEMO-038) (12.3mg, 52%) as a light yellow solid. ¹H NMR (DMSO-d₆, 400 MHz): □ 12.86;(bs, 1H, OH), 10.47; (s, 1H, OH), 8.29; (s, 1H, H-ar), 8.06; (s, 1H,H-ar), 8.05; (d, 2H, J=7.8 Hz, H-ar), 7.84; (d, 1H, J=8.7 Hz, H-ar),7.61; (d, 1H, J=8.0 Hz, H-ar), 7.54; (s, 1H, H-ar), 7.38; (s, 1H, H-ar),7.13; (d, 1H, J=8.6 Hz, H-ar), 3.87; (s, 3H, OCH3), 2.13; (bs, 6H),2.07; (bs, 3H), 1.76; (bs, 6H). ¹³C NMR (DMSO-d₆, 100.6 MHz) □ 167.6,158.5, 153.4, 139.0, 138.1, 132.2, 132.0, 129.7, 128.2, 127.0, 126.0,125.6, 124.9, 121.1, 118.3, 112.8, 107.4, 53.4, 40.1, 36.6, 36.5, 28.4.HRMS (ESI/Q-TDE) m/z calc. for C281-12704 [M−H]⁻ 427.1915, obtained427.1911.

Compound H39

The compound H39 (HEMO-039) of formula:

is prepared according to the following reaction scheme:

(6-(3-(adamantan-1-yl)-4-methoxyphenyl)naphthalen-2-yl)methanol (21)

Boronic acid (2) (150 mg, 0.53 mmol, 1 eq.) was added to a flame-driedmicrowave reactor followed by bromonaphthol (20) (126 mg, 0.53 mmol, 1eq.), Pd(PPh₃)₄ (31 mg, 0.027 mmol, 5 mol %), and K₂CO₃ (146 mg, 1.06mmol, 2 eq.). 10:1 MeOH:H₂O (4.4 mL, 120 mM) was added and the reactorwas sealed. The mixture obtained was stirred at 120° C. for 1 hour inthe microwave. After reaching room temperature, H₂O and CH₂Cl₂ wereadded. The aqueous phase was extracted 3 times with CH₂Cl₂, and thecombined organic phases were washed with saturated NaCl solution, driedover MgSO₄, filtered and concentrated in vacuo. The residue was elutedon a silica gel column with 100% CH₂Cl₂ to obtain (21) (167 mg, 80%) asa white solid. ¹H NMR (CDCl₃, 400 MHz): □ 7.98; (s, 1H, H-ar),7.90-7.82; (m, 4H, 4 H-ar), 7.74; (d, 1H, J=8.5 Hz, H-ar), 7.60; (d, 1H,J=1.7 Hz, H-ar), 7.55-7.48; (m, 2H, 2 H-ar), 6.99; (d, 1H, J=8.4 Hz,H-ar), 4.87; (s, 2H, OCH₂), 3.90; (s, 3H, OCH₃), 2.20; (bs, 6H), 2.11;(bs, 3H), 1.81; (bs, 6H). ¹³C NMR (CDCl₃, 100.6 MHz) □ 158.7, 139.2,139.0, 138.1, 133.4, 133.2, 132.3, 128.6, 128.4, 126.2, 126.0, 125.7,125.6, 125.4, 125.0, 112.2, 65.7, 55.3, 40.8, 37.3, 29.3. HRMS(ESI/Q-TDE) m/z calc. for C₂₈H₃₀O₂ K [M+K]⁺ 437.1877, obtained 437.1869.

(6-(3-(adamantan-1-yl)-4-methoxyphenyl)naphthalen-2y1)methyl)ethanethioate(22)

To a solution of PPh₃ (68 mg, 0.26 mmol, 2 eq.) in THF (500 μl) at 0° C.under argon atmosphere was added di-tert-butyl azodicarboxylate (60 mg,0.26 mmol, 2 eq.) and the resulting solution was stirred for 30 min at0° C. A solution of alcohol (21) (50 mg, 0.13 mmol, 1 eq.) in THF (500μl) was then added and the mixture obtained was stirred for 1 hour at 0°C. then for 1 hour at room temperature. After dilution with CH₂Cl₂, theorganic phase was washed with 1M HCl. The aqueous phase was extracted 3times with CH₂Cl₂ and the combined organic phases were dried over MgSO₄,filtered and concentrated in vacuo. The residue was eluted on a silicagel column with 3:1 CH₂Cl₂:Cyclohexane to obtain (22) (43 mg, 72%) as awhite solid. ¹H NMR (CDCl₃, 400 MHz): □ 7.95; (d, 1H, J=0.6 Hz, H-ar),7.83; (d, 1H, J=8.4 Hz, H-ar), 7.76; (s, 1H, H-ar), 7.72; (dd, 1H, J=1.6Hz, J=8.5 Hz, H-ar), 7.58; (d, 1H, J=2.3 Hz, H-ar), 7.52; (dd, 1H, J=2.3Hz, J=8.4 Hz, H-ar), 7.39; (dd, 1H, J=1.6 Hz, J=8.4 Hz, H-ar), 6.99; (d,1H, J=8.4 Hz, H-ar), 4.30; (s, 2H, SCH₂), 3.90; (s, 3H, OCH₃), 2.38; (s,3H, SAc), 2.19; (bs, 6H), 2.10; (bs, 3H), 1.81; (bs, 6H). ¹³C NMR(CDCl₃, 100.6 MHz) □ 195.3, 158.8, 139.2, 139.0, 134.7, 133.2, 133.1,132.3, 128.8, 128.2, 127.4, 127.3, 126.2, 126.0, 125.7, 124.9, 112.3,55.3, 40.8, 37.3, 34.0, 30.5, 29.3.

(6-(3-(adamantan-1-yl)-4-methoxyphenyl)naphthalen-2-yl)methanesulfonicacid (HEMO-039)

Thioacetate (22) (43 mg, 0.094 mmol, 1 eq.) was suspended in AcOH (1.07mL, 87.5 mM). AcONa (77 mg, 0.94 mmol, 10 eq.) was added, followed bypotassium hydrogen persulfate (74 mg, 0.24 mmol, 2.5 eq.) and themixture obtained was stirred vigorously for 16 h. AcOEt was added andthe precipitate obtained was filtered and washed with AcOEt then theorganic phases were concentrated in vacuo. The residue was eluted on asilica gel column with 0 to 20% MeOH in CH₂Cl₂ to obtain (HEMO-039)(14.5 mg, 33%) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz): □ 8.08; (s,1H, H-ar), 7.89; (d, 1H, J=8.7 Hz, H-ar), 7.86; (d, 1H, J=8.4 Hz, H-ar),7.77-7.74; (m, 2H, 2 H-ar), 7.62; (dd, 1H, J=2.2 Hz, J=8.4 Hz, H-ar),7.56; (d, 1H, J=2.3 Hz, H-ar), 7.52; (dd, 1H, J=1.5 Hz, J=8.4 Hz, H-ar),7.10; (d, 1H, J=8.6 Hz, H-ar), 3.88; (s, 2H, SCH₂), 3.86; (s, 3H, OCH₃),2.14; (bs, 6H), 2.07; (bs, 3H), 1.76; (bs, 6H). ¹³C NMR (DMSO-d₆, 100.6MHz) □ 158.2, 137.9, 137.1, 133.1, 132.3, 132.1, 131.7, 129.4, 128.1,128.0, 126.9, 125.4, 124.8, 123.9, 112.7, 57.7, 55.3, 36.6, 28.4. HRMS(ESI/Q-TDE) m/z calc. for C₂₈H₂₉O₄S [M−H]⁻ 461.1792, obtained 461.1784.

Example 4—Synthesis of Compound H24

The compound H24 of formula:

is prepared according to the following reaction scheme:

Methyl 3′-(adamantan-1-yl)-4′-methoxy[1,1′-biphenyl]-4-carboxylate (3)

Boronic acid (2) (242 mg, 0.85 mmol, 1 eq.) was added to a flame-driedreactor followed by methyl 4-bromobenzoate (1) (183 mg, 0.85 mmol, 1eq.), Pd(PPh₃)₄ (54 mg, 0.047 mmol, 5 mol %), and K₂CO₃ (257 mg, 1.86mmol, 2 eq.). After addition of 10:1 MeOH:H₂O (7.75 mL, 120 mM) thereactor was sealed. The solution was then stirred at 80° C. for 16 h.After reaching room temperature, H₂O and CH₂Cl₂ were added. The aqueousphase was extracted 3 times with CH₂Cl₂, and the combined organic phaseswere washed with saturated NaCl solution, evaporated over MgSO₄,filtered and concentrated in vacuo. The residue was eluted on a silicagel column with 1:2 CH₂Cl₂:Cyclohexane to give (3) (260 mg, 85%) as awhite solid. ¹H NMR (CDCl₃, 400 MHz): □ 8.07; (d, 2H, J=8.4 Hz, 2 H-ar),7.63; (d, 2H, J=8.4 Hz, 2 H-ar), 7.50; (d, 1H, J=2.3 Hz, H-ar), 7.45;(dd, 1H, J=2.3 Hz, J=8.4 Hz, 2 H-ar), 6.96; (d, 1H, J=8.4 Hz, H-ar),3.93; (s, 3H, CH₃), 3.89; (s, 3H, CH₃), 2.15; (bs, 6H), 2.09; (bs, 3H),1.79; (bs, 6H). ¹³C NMR (CDCl₃, 100.6 MHz) □ 167.3, 159.3, 146.2, 139.1,132.1, 130.2, 128.1, 126.7, 125.9, 125.7, 112.2, 55.3, 52.2, 40.7, 37.2,29.2, 27.1. HRMS (ESI/Q-TDE) m/z calc. for C₂₅H₂₉O₃ [M+H]⁺ 377.2111,found 377.2111.

2-(3′-(adamantan-1-yl)-4′-methoxy-[1,1′-biphenyl]-4-ylcarboxam ido)methyl acetate (4)

To a suspension of ester (3) (112 mg, 0.31 mmol) in 2:1 THF:H₂O (4.3 mL)was added LiOH (19 mg, 0.78 mmol, 2.5 eq.). After mixing for 18 h, 1MHCl was added to reach pH=1. The precipitate formed was filtered, washedwith H₂O and evaporated in vacuo before being suspended in anhydrousCH₂Cl₂ (7.5 ml). EDC.HCl (140 mg, 0.73 mmol, 2.5 eq.), HOBt (120 mg,0.87 mmol, 3 eq.) and DIPEA (200 μl, 1.15 mmol, 4 eq.) were then addedand the mixture obtained was stirred for 5 min at room temperaturebefore the addition of glycine methyl ester (74 mg, 0.58 mmol, 2 eq.).After stirring for 16 h, 1M HCl was added and the aqueous phase wasextracted 3 times with CH₂Cl₂. The combined organic phases were washedwith H₂O and saturated NaCl solution, evaporated over MgSO₄, filteredand concentrated in vacuo. The residue was eluted on a column of silicagel with 30 to 50% AcOEt in Cyclohexane to obtain (4) (97 mg, 74%) as awhite solid. ¹H NMR (CDCl₃, 500 MHz): □ 7.87; (d, 2H, J=8.3 Hz, 2 H-ar),7.64; (d, 2H, J=8.3 Hz, 2 H-ar), 7.48; (d, 1H, J=2.2 Hz, H-ar), 7.44;(dd, 1H, J=2.3 Hz, J=8.4 Hz, 2 H-ar), 6.96; (d, 1H, J=8.4 Hz, H-ar),6.68; (bs, 1H, NH), 4.28; (d, 2H, J=4.9 Hz, NCH₂) 3.89; (s, 3H, CH₃),3.82; (s, 3H, CH₃), 2.15; (bs, 6H), 2.09; (bs, 3H), 1.79; (bs, 6H). ¹³CNMR (CDCl₃, 125.7 MHz) □ 170.8, 167.5, 159.2, 145.2, 139.1, 132.0,131.5, 127.7, 126.9, 125.8, 125.6, 112.2, 55.3, 52.6, 41.9, 40.7, 37.3,37.2, 29.2. HRMS (ESI/Q-TDE) m/z calc. for C₂₇H₃₂NO₄ [M+H]⁺ 434.2326,obtained 434.2322.

2-(3′-(adamantan-1-yl)-4′-methoxy-[1,1′-biphenyl]-4-ylcarboxamido)aceticacid (HEMO-024, or H24)

To a suspension of ester (4) (25 mg, 0.058 mmol) in 2:1 THF:H₂O (1.5 mL)was added LiOH (4 mg, 0.15 mmol, 2.5 eq.). After stirring for 18 h, 1MHCl was added to reach pH=1. The precipitate formed was filtered, washedwith H₂O and evaporated in vacuo to obtain (HEMO-024) (13 mg, 54%) as awhite solid. ¹H NMR (DMSO-d₆, 400 MHz): □ 12.57; (bs, 1H, OH), 8.84; (t,1H, J=5.9 Hz, NH), 7.93; (d, 2H, J=8.4 Hz, 2 H-ar), 7.72; (d, 2H, J=8.4Hz, 2 H-ar), 7.55; (dd, 1H, J=1.9 Hz, J=8.4 Hz, H-ar), 7.46; (d, 1H,J=1.9 Hz, H-ar), 7.08; (d, 1H, J=8.6 Hz, H-ar), 3.94; (d, 2H, J=5.8 Hz,NCH₂), 3.85; (s, 3H, OCH₃), 2.11; (bs, 6H), 2.06; (bs, 3H), 1.75; (bs,6H). ¹³C NMR (DMSO-d₆, 125.7 MHz) □ 171.4, 166.3, 158.7, 143.4, 138.0,131.7, 131.1, 127.9, 126.0, 125.5, 124.8, 112.7, 55.4, 41.2, 36.6, 28.4.HRMS (ESI/Q-TDE) m/z calc. for C₂₆H₂₈NO_(4 [)M−H]⁻ 418.2024, obtained418.2016.

Example 5—Ex Vivo Thrombin Generation Assay

A second thrombin generation test is carried out, for the compounds H27,H31, H32, H35, H38, H39 and the compound H24.

The thrombin generation test was carried out at 37° C. using a CATanalyzer (Diagnostica Stago) with the PPP Reagent LOW reagent(Diagnostica Stago) in accordance with the manufacturer's instructionsand according to the method established by Pr. Hemker in 2003. PPPReagent LOW is a mixture of tissue factor (TF) 1 pM with phospholipidvesicles (PL, 4 μM). The test is triggered by the addition of a mixtureof calcium+fluorescent substrate (ZGGR-AMC) (FluCa mixture).

From a technical point of view, 80 μL of surcharged plasma sample isadded to 20 μL of «initiator complex» (PPP Reagent LOW) and incubatedfor 10 min at 37° C. Then, the reaction is triggered by adding 20 μL ofFluCa (mixture of CaCl₂ and ZGGR-AMC substrate) and the fluorescencesignal is measured over time. Each test is performed in triplicate.

For each tested molecule, 247 μL of plasma from the hemophiliac patientwere surcharged with 13 μL of a solution containing different amounts ofcompound (molecule to be tested, factor VIII or dilution buffer) toobtain the desired final concentration (systematic dilution of themolecule to be tested in the plasma at 1/20). For example, to obtain thefinal concentration of 50 μM in plasma, 13 μL of a 1 mM solution wasadded to 247 μL of plasma. In parallel with the tests on the differentchemical compounds, the plasma of a hemophiliac patient is surchargedwith the same buffer for diluting the compound, an 8% solution ofdimethyl sulfoxide (DMSO), as a negative control (0.4% of final DMSO) inorder to obtain the basal level of thrombin generation of the usedplasma. The positive control is the same plasma surcharged with plasmafactor VIII (Factane, LFB, France) at a concentration of 1 IU/mL (or100% factor VIII) in order to obtain the expected «normal» level ofthrombin generation used plasma.

For this example, solutions of adapalene and 1 mM compounds wereprepared with the buffer (18 mM HEPES, 135 mM NaCl, pH 7.35) instead ofwater as in Example 1. This modification has made it possible toincrease the amount of thrombin generated by the plasma of thehemophiliac patient A in the presence of 50 μM of adapalene.

Compounds were tested at a final concentration of 50 μM in plasma, andsignal was measured over time. The obtained results, expressed as theamount of thrombin measured at the maximum of the peak obtained andnormalized to the thrombin peak obtained with adapalene, are shown inTable 1 below:

TABLE 1 Negative Positive Compound Ad H24 H27 H31 H32 H35 H38 H39control control Amount of 1 0.23 0.51 0.62 0.55 0.53 0.96 1.22 0.13 ±0.28 ± thrombin 0.02 0.06

All the tested compounds according to the invention make it possible toobtain a significant increase in the generation of thrombin compared tothe negative control, with, for all of them except the compound H24, apeak of generated thrombin higher than that of the control positive, andin particular much higher for the compounds Ad, H38 and H39.

1. A method of treating hemophilia comprising administering a compoundof a general formula (III′) or a pharmaceutically acceptable saltthereof to a subject suffering from hemophilia:

in which Y₁′ represents a covalent bond or an amide group, R₄′represents a hydrogen atom, a hydroxyl group, a halogen atom, an aminegroup or a linear or branched, saturated or unsaturated carbon radical,which is optionally interrupted and/or substituted by one or moreheteroatoms and/or one or more several groups including at least oneheteroatom, Y₂′ represents a covalent bond or an amide group, A₂′represents an optionally substituted cyclic or heterocyclic groupincluding two fused rings, at least one of said rings being aromatic. 2.The method according to claim 1, for the restoration of coagulation inthe plasma of the subject suffering from hemophilia.
 3. The methodaccording to claim 2, for the restoration of the generation of thrombinin the plasma of the subject suffering from hemophilia.
 4. The methodaccording to claim 1, according to which, in the general formula (III′),R₄′ represents an —OR₈ group or an —O—CO—R₈ group, where R₈ represents alinear or branched, saturated or unsaturated hydrocarbon radical,including from 1 to 10 carbon atoms, optionally substituted by one ortwo identical or different substituents R₁₄, R₁₄′, each selected from—F, —CO₂H, —SO₃H, —P(O)(OH)₂, —P(O)(OCH₃)₂, —P(O)(OCH₃)₂,—P(O)(OCH₂CH₃)₂, —N(CH₃)₂, —N(CH₂—CH₃)₂,

where R15 represents a hydrogen atom or a methyl group.
 5. The methodaccording to claim 4, according to which R₈ represents a group ofgeneral formula (XVIII):

wherein y is an integer comprised between 1 and 10 and R₁₄ is as definedin claim
 4. 6. The method according to claim 1, according to which, inthe general formula (III′), R₄′ is fixed to the phenyl radical in theortho or para position with respect to the adamantyl unit, and Y₂′ isfixed to the phenyl radical in the meta position relative to theadamantyl unit.
 7. The method according to claim 1, according to which,in the general formula (III′), A₂′ is at least substituted by onesubstituent R₁₁ selected from fluorine, carboxyl, sulphonyl, phosphonyl,tetrazole or keto-oxadiazole, and linear, branched and/or cyclic,saturated or unsaturated, aromatic or non-aromatic carbon radicals,optionally interrupted and/or substituted by one or more heteroatoms,and/or one or more groups comprising at least a heteroatom.
 8. Themethod according to claim 7, according to which R₁₁ is selected from thegroups of formulas:


9. The method according to claim 1, said compound corresponding to thegeneral formula (IX):

wherein Y₁′, Y₂′ and R₄′ are as defined in claim 1, A₃ represents acyclic or 3- to 8-membered heterocyclic, saturated or unsaturated,aromatic or not hydrocarbon, B₁ and B₂, which are identical ordifferent, each represent a —CH— group or a nitrogen atom, R₉ and R₁₀,which are identical or different, each represent a hydrogen atom, ahydroxyl group or an —OR₁₂ or —CO—O—R₁₂ group where R₁₂ represents alinear or branched, saturated or unsaturated hydrocarbon radical,including 1 to 10 carbon atoms, optionally substituted by one or twoidentical or different substituents R₁₆, R₁₆′, each selected from —F,—CO₂H, —SO₃H, —P(O)(OH)₂, —P(O)(OCH₃)₂, —P(O)(OCH₂CH₃)₂, —N(CH₃)₂,—N(CH₂—CH₃)₂,

where R₁₇ represents a hydrogen atom or a methyl group, and R₁₁represents a substituent selected from fluorine, carboxyl, sulphonyl,phosphonyl, tetrazole or keto-oxadiazole groups, and linear, branchedand/or cyclic, saturated or unsaturated, aromatic or not carbonradicals, which are optionally interrupted and/or substituted by one ormore heteroatoms, and/or one or more groups including at least oneheteroatom.
 10. The method according to claim 9, wherein R11 representsa —(CH₂)_(x)—R₁₃ group where x is an integer comprised between 0 and 4and R13 represents a fluorine atom or a carboxyl, sulfonyl, phosphonyl,tetrazole or keto-oxadiazole group.
 11. The method according to claim10, said compound corresponding to the general formula (X):


12. The method according to claim 10, said compound corresponding to thegeneral formula (XI):


13. The method according to claim 10, said compound corresponding to thegeneral formula (XII):


14. The method according to claim 10, said compound corresponding to thegeneral formula (XIII)


15. The method according to claim 10, said compound corresponding to thegeneral formula (XIV):


16. The method according to claim 10, said compound corresponding to thegeneral formula (XV):


17. The method according to claim 10, said compound corresponding to theformula (XVI):


18. The method according to claim 1, said compound corresponding to theformula (V):


19. The method according to claim 1, said compound corresponding to theformula (XVII):


20. The method according to claim 1, wherein said subject is a mammal.21. The method according to claim 1, wherein said compound is containedin a pharmaceutical composition, in a pharmaceutically acceptablevehicle.
 22. The method according to claim 21, wherein said compositionis in a form suitable for administration to said subject by oral route.